Abstract:Recent technological developments, such as single unit recordings coupled to optogenetic approaches, have provided unprecedented knowledge about the precise neuronal circuits contributing to the expression and recovery of conditioned fear behavior. These data have provided an understanding of the contributions of distinct brain regions such as the amygdala, prefrontal cortex, hippocampus, and periaqueductal gray matter to the control of conditioned fear behavior. Notably, the precise manipulation and identification of specific cell types by optogenetic techniques have provided novel avenues to establish causal links between changes in neuronal activity that develop in dedicated neuronal structures and the short and long-lasting expression of conditioned fear memories. In this review, we provide an update on the key neuronal circuits and cell types mediating conditioned fear expression and recovery and how these new discoveries might refine therapeutic approaches for psychiatric conditions such as anxiety disorders and posttraumatic stress disorder.

Abstract:PURPOSE: To determine whether modification of the connections between cerebellar and prefrontal areas might vary among multiple sclerosis (MS) phenotypes and might be associated with cognitive failure. MATERIALS AND METHODS: Approval of the institutional review boards and written informed consent were obtained from each participant. Stroop-related functional magnetic resonance (MR) imaging activations and effective connectivity abnormalities between the right cerebellum and any other brain regions were assessed by using a psychophysiologic interaction (PPI) analysis from 17 patients with relapsing-remitting (RR), 17 with benign, and 23 with secondary progressive (SP) MS and 18 healthy control subjects (P < .05, corrected at cluster level). Correlations with disease duration, T2 lesion volume, brain volume, and response times (RTs) during the incongruent condition were estimated (P < .001, uncorrected). RESULTS: Activation and PPI analyses showed that, compared with the other groups, RR MS group had abnormal recruitment of regions of the left frontoparietal lobes, whereas compared with RR MS group, SP MS group had abnormal recruitment of the cingulum or precuneus. Benign MS group had increased activation of the right prefrontal cortex, and increased interaction between these regions and the right cerebellum. In healthy controls, RTs inversely correlated with activity of right cerebellum and several frontoparietal regions. In MS, RTs inversely correlated with bilateral cerebellar activity and directly correlated with right precuneus activity. In MS, disease duration inversely correlated with right cerebellar activity and directly correlated with left inferior frontal gyrus and right precuneus activity. Higher T2 lesion volume and lower brain volumes were related to activity in these areas. CONCLUSION: Patients with MS who have various clinical phenotypes experience different abnormalities in activation and effective connectivity between the right cerebellum and frontoparietal areas, which contribute to inefficient cortical reorganization, with increasing cognitive load. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12120216/-/DC1.

Abstract:Cognition is frequently impaired in the early stages of multiple sclerosis (MS). The predictive value of cognitive impairment on disability is unknown. The objective of this study was to correlate cognitive impairment and the progression of disability over 7 years. Forty-five patients, recruited after MS diagnosis, were followed for 7 years by yearly Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC) evaluations and were classified as cognitively impaired (CI) or unimpaired (CU) according to neuropsychological testing at baseline. At baseline, 47.8% of patients were CI, with deficits in mainly memory and information processing speed (IPS). The baseline EDSS correlated significantly with one IPS test. The EDSS, but not the MSFC, deteriorated significantly over the 7 years in the whole group and the CI group, but not the CU group. A multivariate analysis showed correlations between the EDSS change over 5 and 7 years and two baseline tests evaluating IPS and verbal memory. The deterioration of the EDSS after 7 years was significantly correlated with verbal memory testing at baseline after adjustment for age and baseline EDSS. In conclusion, in this sample of MS patients early in the disease, the baseline IPS and verbal memory impairments predict the EDSS score 5 and 7 years later.

Abstract:Recent imaging studies have evidenced various cerebral patterns dependent on
educational level during cognitive tasks in neurodegenerative diseases. Determining relationships between educational status and cerebral activation during cognitive demands in physiological conditions may help to better understand the role of education on cognitive efficacy and functional reorganisation in pathological conditions. We proposed to analyse by functional MRI (fMRI) the relationship between educational status and cerebral activation during various attentional requests in healthy young adults. Twenty healthy young adults completed four successive conditions of a Go/No-go test of increasing complexity under fMRI. An effect of education was observed on attentional performances. Both in-scanner response times and cerebral activation increased during the Go/No-go paradigm. Healthy subjects with higher education exhibited higher activity in cerebellum and lower activity in medial prefrontal and inferior parietal regions compared with the healthy subjects with lower educational levels while performing the conditions of Go/No-go task. Our data evidence the influence of education on automatized strategies in healthy adults by modulating a functional balance of activation between cerebral cortex and cerebellar regions during attentional processes.

Abstract:BACKGROUND: Pain is a frequent symptom during the course of multiple sclerosis
(MS) but its frequency and impact at the early clinical stages remain unknown. OBJECTIVES: The aim of this study was to establish prevalence and severity of pain in a cohort of patients recently diagnosed with MS and to determine the evolution of pain prevalence over 2 years. Other objectives were to investigate the presence of baseline clinical predictors of pain after 2 years and to establish its impact on quality of life (QOL). METHODS: In a population-based sample of 69 patients recently diagnosed with MS (<6 mo), pain was measured using questions from the SEP-59 QOL questionnaire. A standardized bedside neurologic examination was performed to establish sensory function, sensory Kurtzke functional system score, and disability scales. Patients were reassessed after 1 and 2 years. RESULTS: Pain was reported by 73.5% of MS patients at baseline and by 70.6% and 61.8% at 1 and 2-year follow-ups, respectively. Clinically significant pain (grades between 3 and 6 using a 6-graded verbal scale) was reported by 63.2% of patients at baseline and by 51.5% and 45.6%, at 1 and 2-year follow-ups, respectively. Pain significantly altered daily activities in 44% of patients. Low overall QOL scores were significantly associated with pain. At 2 years time point, occurrence of pain was associated with baseline depressive symptoms after controlling for the presence of pain at baseline. CONCLUSIONS: Pain is frequent in the early stages of MS and affects the daily QOL.

Abstract:BACKGROUND: The multiple sclerosis functional composite (MSFC) includes the Paced Auditory Serial Addition test (PASAT) as a measure of cognition. OBJECTIVES AND METHODS: We compared the MSFC incorporating the Symbol Digit Modalities test (SDMT) (MSFC [sdmt]) to the usually applied MSFC (MSFC [pasat]) in a sample of 46 ptients with relapsing-remitting MS who were followed over a five-year period. Magnetic resonance imaging was performed at baseline. RESULTS: The Expanded Disability Status scale (EDSS) deteriorated significantly over 5 years (P < 0.01), but MSFC scores remained stable. MSFC [sdmt] correlated with EDSS at all time points of evaluation, but MSFC [pasat] correlated with EDSS only at baseline, 1, and 5 years. The 5-year EDSS correlated significantly with baseline MSFC [sdmt] and MSFC [pasat] but did not correlate after adjustment for baseline EDSS. No significant correlation was found at baseline between MSFC and imaging parameters (lesion load, brain parenchymal fraction [BPF], ventricular fraction, mean magnetization transfer ratio of lesions and normal-appearing brain tissue), but baseline BPF correlated significantly with changes of SDMT z score (P = 0.0003), MSFC [pasat] (P = 0.006), and MSFC [sdmt] (P = 0.0002) over 5 years. CONCLUSION: We propose not to substitute PASAT by SDMT in the MSFC but to consider SDMT as a complementary useful approach to evaluate overall MS disease.

Abstract:Forty to sixty percent of patients with multiple sclerosis (MS) have cognitive dysfunction. The frequency of cognitive disturbances according to the clinical form is not completely understood and the natural history of these disorders has not been extensively studied. Cognitive deficits can be detected in early stages of the disease. Their frequency increases from clinically isolated syndromes, to relapsing-remitting and secondary progressive MS. Cognitive abnormalities are frequently observed also in primary progressive MS. The most frequently impaired functions are information processing speed, attention and memory. Dementia is uncommon but may disclose the disease. Diffuse cerebral injury, assessed by magnetic resonance imaging, contributes to cognitive dysfunction in MS, probably by interrupting connecting fibers between neuronal networks involved in these cognitive functions. Compensatory mechanisms may occur at early stages but they are limited by extension of brain injury.